Critical Periods of Recovery from Hearing Loss in the Developing Auditory Cortex

发育中的听觉皮层听力损失恢复的关键时期

• 批准号: 8889867
• 负责人: Todd M. Mowery
• 金额: $ 0.17万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889867
• 关键词: Action Potentials; Adult; Affect; Age; Age of Onset; Animals; Auditory; Auditory area; Basic Science; Bilateral; Brain; Cognitive; Data Analyses; Data Collection; Development; Ear; Earplug; Excision; Goals; Health; Hearing; Human; Kinetics; Language Development; Measures; Membrane; Membrane Potentials; Neuraxis; Process; Property; Proteinase 3; Recovery; Recovery of Function; Resistance; Rest; Sensory; Sensory Deprivation; Slice; Synapses; Synaptic Membranes; Testing; Time; Whole-Cell Recordings; critical period; hearing impairment; hippocampal pyramidal neuron; human TFRC protein; neuronal excitability; postnatal; relating to nervous system; remediation; research study; restoration; voltage clamp

DESCRIPTION (provided by applicant): Developmental hearing loss (HL) can induce profound changes to auditory processing and cognitive processes, such as language acquisition. This is because the central nervous system is particularly vulnerable to disruptions of sensory activity during discrete intervals prior to adulthood. These intervals are often referre to as critical periods (CP). Consistent with basic research findings, early remediation of hearing loss in humans is highly correlated with recovery of normal function. This suggests that the critical period concept applies to human hearing loss. The core hypothesis of this proposal is that recovery from hearing loss-induced changes to cortical membrane and synaptic properties depends on the restoration of hearing prior to the closure of one or more critical periods. The key goals of this proposal are to determine the CPs during which mild hearing loss (i.e., bilateral earplugs), or the restoration of normal hearing (i.e., earplug removal) during development will influence cellular properties in auditory cortex. Both the onset of earplug insertion and the time of earplug removal will be varied as a function of postnatal age to explore the timing and termination of auditory CPs. Two key cellular properties that contribute to neuronal excitability will be assessed in the auditory cortex: (1) Membrane and firing properties, and (2) Inhibitory synaptic currents. There are two experimental Aims. Aim 1 asks whether there is more than one CP during which hearing loss affects cellular properties. To determine whether there are CPs for mild hearing loss, animals will be reared with bilateral earplugs and the age-of-onset for EP insertion will be varied. Whole-cell recordings will be obtained from layer 2/3 pyramidal neurons in thalamocortical brain slices from earplug-reared and age-matched unmanipulated animals. Current-clamp recordings will be used to measure membrane properties and voltage-clamp recordings will be used to measure spontaneous and evoked inhibitory synaptic currents. These measures will reveal whether there are multiple CPs during which specific cortical properties are sensitive to hearing loss. Aim 2 asks whether there is a critical period during which hearing restoration permits recovery of cellular properties. Therefore, animals will be reared with bilateral EPs and the age of EP removal will be varied throughout development. To evaluate the effects of earplug removal, whole cell recordings will be obtained in animals with restored hearing and age- matched controls. All data collection parameters and analytical approaches will be identical to Aim 1. The experiment will allow me to distinguish whether the critical period for EP insertion and removal occur within the same age window, or whether the critical periods for removal depend on the age of EP insertion. Together, these findings will reveal whether there are discrete critical periods for the maturation of cellular properties, and suggest whether there are optimal periods for remediation of developmental hearing loss.

描述（由申请人提供）：发育听力损失（HL）可以引起听觉处理和认知过程（例如语言获取）的深刻变化。这是因为中枢神经系统在成年前的离散间隔期间特别容易受到感觉活动的破坏。这些间隔通常称为关键时期（CP）。与基础研究结果一致，早期修复人类的听力损失与正常功能的恢复高度相关。这表明关键时期概念适用于人类听力损失。该提案的核心假设是，从听力损失引起的皮质膜变化中恢复，突触特性取决于在关闭一个或多个关键时期之前的听力恢复。该提案的主要目标是确定轻度听力损失的CP（即双边 耳塞），或在发育过程中恢复正常听力（即耳塞去除）将影响听觉皮层的细胞性质。耳塞插入的发作和耳塞去除时间都将随着产后年龄的函数而变化，以探索听觉CP的时间和终止。在听觉皮层中将评估有助于神经元兴奋性的两个关键细胞特性：（1）膜和触发特性，以及（2）抑制性突触电流。有两个实验目标。 AIM 1询问是否有多个CP在其中听力损失会影响细胞性质。为了确定是否有轻度听力损失的CP，将用双侧耳塞饲养动物，并且EP插入的年龄将有所不同。全细胞记录将从丘脑皮质脑切片中的2/3层锥体神经元中获得，并从耳塞奔跑和年龄匹配的无操纵动物中获得。电流钳记录将用于测量膜性能，并且电压钳记录将用于测量自发和引起抑制性突触电流。这些措施将揭示是否有多个CP，在此中，特定皮质特性对听力损失敏感。 AIM 2询问听力恢复是否允许恢复细胞性质的关键时期。因此，动物将饲养双侧EPS，并且EP去除的年龄在整个发育过程中都会有所不同。为了评估耳塞去除的影响，将在具有恢复听力和年龄匹配的对照的动物中获得全细胞记录。所有数据收集参数和分析方法都将与目标1相同。该实验将使我能够区分EP插入和去除的关键时期是否发生在同一年龄窗口内，或者关键删除的关键时期是否取决于EP插入的年龄。总之，这些发现将揭示是否存在分散的细胞性质成熟时间，并提出是否有最佳的修复发育听力损失的时期。